Systematic review and meta-analysis

Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

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Gene expression profiling predicts clinical outcome of breast cancer

Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

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A Gene-Expression Signature as a Predictor of Survival in Breast Cancer

Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. Methods: Women (N = 13 388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35‐59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Gail’s algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50‐59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles’), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35‐4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease. [J Natl Cancer Inst 1998;90:1371‐88]

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Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

Background We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclit...

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Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

Editor—Suzanne Fletcher concludes an otherwise excellent editorial on breast cancer screening in women younger than 50 by stating: “As time goes on and questions remain about the usefulness of screening women in their 40s for breast cancer, the wisdom of the organisers of the British trial becomes increasingly apparent.”1 I would like to make a mathematical estimate of …

Breast cancer screening for younger women is not an efficient use of resources.

Behavioral testing methods are described for determining whether female mice can discriminate between volatile urinary pheromones of conspecifics of the same vs. opposite sex and/or in different endocrine conditions, for determining sexual partner preference, for quantifying receptive (lordosis) behavior, and for monitoring the expression of male-typical mounting behavior in female mice.

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Assessment of urinary pheromone discrimination, partner preference, and mating behaviors in female mice.

Background: One third of breast cancers are now diagnosed in women aged 70 or over. With its high median age at study entry (64 years) the ATAC study (1) represents an opportunity to characterise tumour and treatment characteristics of a cohort of older women with early breast cancer. It also enables us to examine the effects co-morbidities and age on competing causes of mortality which could have a significant influence on adjuvant treatment decisions. Materials and Methods: Details of trial design, methods and outcome have been published in detail elsewhere (1). The current analysis was based on the 100-month median follow-up data in the safety population in the two monotherapy arms (anastrozole N=3092, tamoxifen N=3094). Baseline co-morbidities, tumour and treatment characteristics were comparedbetween those aged Results: 1662 patients (27%) were aged 70 or over at study entry. Women aged 70 or over had larger tumours compared with younger women (≥2cm: 56.8 vs. 67.6%, OR 0.63, [95%CI 0.56-0.71]). Older women were more likely to undergo mastectomy (OR 1.92 [95%CI 1.71-2.16]), less likely to receive radiotherapy (OR 0.49 [95%CI 0.44-0.55]), or chemotherapy (OR 0.24 [95%CI 0.18-0.29]). Women aged 70 or over had higher rates of co-morbidities irrespective of index used. Women aged 70 or over had an increased risk of recurrence compared with those less than 70: 20.2% vs. 18.7% (HR 1.21, [95%CI 1.09-1.38]), and an increased risk of death without recurrence: 17.9% vs. 5.2% (HR 4.03 [95%CI 3.39-4.78]). The risk of death without recurrence increased with increasing co-morbidity score: 5.8% vs. 14.4% vs. 21.7% for Satariano score 0, 1 and 2+ respectively (P Discussion: There are differences in tumour and treatment characteristics between older and younger patients which may explain the differences in risks of recurrence. Age and co-morbidities significantly influence the risks of death without recurrence. Formal assessment of co-morbidities should be incorporated into decisions regarding adjuvant therapies. 1. ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-03.

Abstract P5-13-03: The Influences of Co-Morbidities and Age on Risk of Death without Recurrence: A Retrospective Analysis of the ATAC Trial

Does preoperative MRI influence the extent of surgical resection in conservative breast cancer surgery

SIR,-While agreeing with Dr. H. J. G. Bloom and others (25 July, p. 181) that the results of radical treatment for medullary carcinoma of the breast are remarkably good we cannot accept the validity of two of their conclusions. Firstly, there is insufficient evidence to support their view that conservative treatment would not have achieved similar results as compared with a radical approach. In their non-randomized retrospective study only 14 patients out of 104 had either a simple mastectomy or wedge excision. Of these 10 also had postoperative radiotherapy. No attempt was made to explain why the policy of radical surgery was abandoned in these cases. We believe that it is not possible to reach a reasonable conclusion on the results of conservative surgery alone on the basis of four patients. Secondly, we feel that it is very difficult for the authors to make judgements on the importance of the role of possible local defence mechanisms in medullary carcinoma of the breast. This would entail a prospective randomized trial comparing the results of radical treatment, which would involve ablation of the lymph nodes by surgery or radiotherapy, with conservative surgery by itself, which would result in the least interference with regional lymph nodes. Taking cancer of the breast as a whole there is increasing evidence of the importance of local defence mechanisms.' We would agree wholeheartedly with Dr. Bloom and his colleagues when they say that the value of treating the axilla in the initial therapy of early breast cancer awaits the results of well-conducted clinical trials where the comparison of radical and conservative therapy can be made on secure foundations.1-We are, etc., MICEuEL BAUM. M. H. EDWARDS. King's Colleee Hosoital Medical School, London S.E.5.

https://www.bmj.com/content/bmj/3/5721/521.2.full.pdf

Michael J. Baum

Papers

Breast cancer screening for younger women is not an efficient use of resources.

Assessment of urinary pheromone discrimination, partner preference, and mating behaviors in female mice.

Abstract P5-13-03: The Influences of Co-Morbidities and Age on Risk of Death without Recurrence: A Retrospective Analysis of the ATAC Trial

Does preoperative MRI influence the extent of surgical resection in conservative breast cancer surgery

Medullary Carcinoma of Breast